Mutations in cancer susceptibility genes are the primary cause of heritable cancers. In sporadic tumors, multiple small sequence changes in a tumor suppressor gene(s) complete one of the steps towards malignancy. The purpose of this proposal is to address whether the higher incidence and mortality of specific cancers (e.g., breast, uterine and prostate) in the African-American population are associated with an increased frequency of mutations in cancer susceptibility genes, which may contribute to the genesis and poor prognosis of their disease. The specific aims of this proposal are: (1) To analyze the genetic alterations in DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPSM2) in breast, uterine and prostate tumors (benign and malignant) derived from minorities; (2) To determine the frequency of mutations in the BRCA1 gene from primary breast carcinomas. Genetic mutations in cancer susceptibility genes will be detected by screening DNA and RNA from tumors by single-strand conformation polymorphism analysis and direct sequencing. These studies will define some of the genetic changes that occur during the process of tumorigenesis. As cancer susceptibility genes have the potential to be used in genetic screening in the future, analyzing the range of mutations that occur in different ethnic groups will have important implications for public health and cancer prevention. The long term goal of this project will be to study other tumor biologic factors which may contribute to the higher incidence of cancer in African-Americans.